Candesartan, an angiotensin receptor blocker, prevents cognitive impairment in female mice with mammary cancer.

Cancer-related cognitive impairment affects a substantial proportion of cancer patients, significantly reducing quality of life and interfering with daily functioning. Neuroinflammation, oxidative stress, and blood-brain barrier (BBB) dysfunction are mechanistic contributors to cancer-related cognitive impairment. Evidence suggests that dysregulation of the renin-angiotensin system (RAS) is involved, as it modulates these biological processes, and pathway analyses demonstrate that perturbations in gene expression of RAS components in the peripheral blood distinguish cancer patients who experience cognitive symptoms from those who do not. To explore the potential of repurposing angiotensin receptor blockers for cancer-related cognitive impairment, we tested whether candesartan, an angiotensin II type 1 receptor (AT1R) antagonist, could prevent cancer-induced cognitive deficits and alter RAS-related gene expression, cytokine mRNA levels, and BBB integrity. Using the 4T1.2 mammary cancer model, we assessed spatial memory and object recognition and examined molecular changes in the prefrontal cortex and hippocampus. Candesartan blocked cancer-induced spatial memory impairment without affecting primary tumour growth or causing sickness behaviour. Candesartan's efficacy was associated with reduced hippocampal and cortical angiotensin II type 1a receptor (Agtr1a) and cortical angiotensin II type 1b receptor (Agtr1b) expression, alongside increased hippocampal angiotensin II type 2 receptor (Agtr2), consistent with a shift toward a neuroprotective RAS signalling profile. Candesartan lowered tumour necrosis factor (Tnf) expression and improved BBB integrity in the frontal cortex, supporting its anti-inflammatory role. We provide the first evidence that candesartan may offer a low-cost strategy to prevent cancer-related cognitive impairment by modulating the RAS, neuroinflammation and BBB permeability.